Peripheral Nervous System Pain Modulation.

The percutaneous technique of electrode insertion in the vicinity of the greater occipital nerves to treat occipital neuralgia was first described in the 1990s by Weiner and Reed. This subsequently stimulated awareness of peripheral nerve stimulation (PNS). The more recent advent emergence of a minimally invasive percutaneous approach by way of using ultrasound has further increased the interest in PNS as a viable alternative to more invasive techniques. PNS has become more popular recently and is increasingly used to treat various pain conditions. Its foundation is fundamentally based on the gate control theory, although the precise mechanism underlying its analgesic effect is still indefinite. Studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and the involvement of the cortical and subcortical areas. Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the modulation of PNS mechanisms can help guide stimulation approaches and parameters to optimize the use of PNS. his chapter aims to review the background and mechanisms of PNS modulation. PNS is becoming one of the most diverse therapies in neuromodulation due to rapid evolution and expansion. It is an attractive option for clinicians due to the simplicity and versatility of procedures that can be combined with other neuromodulation treatments or used alone. It has a distinct role in the modulation of functional conditions.

Does hyperbaric oxygen therapy facilitate peripheral nerve recovery in upper extremity injuries? A prospective study of 74 patients.

PURPOSE: Several experimental studies have investigated the effects of hyperbaric oxygen therapy (HBOT) on peripheral nerve regeneration. However, to the best of our knowledge, clinical studies to evaluate the effects of HBOT on peripheral nerve recovery are seldom performed. The aim of our study was to investigate the efficacy of HBOT following primary nerve repair in patients with upper extremity nerve injuries. METHODS: Patients admitted to our hospital between 2015 and 2019 with ulnar and median nerve injuries were included in the study. Patients were randomized based on their application dates and divided into two different groups. Patients who received HBOT following standard epineural nerve repair were included in group 1, while patients who only underwent epineural nerve repair were included in group 2. All patients were followed up at 3, 6, and 12 months post-treatment and evaluated through electroneuromyography analysis of the traumatized nerve, injured nerve-related muscle strength, and two-point discrimination test. RESULTS: Impulse transmission of injured nerves to the end organ was faster in group 1. Further, ENMG parameters demonstrated that injured nerves of patients in group 1 recovered faster. Patients in group 1 also reached higher power score and had significantly more rapid motor recovery than patients in group 2. CONCLUSION: This prospective study of upper extremity injuries demonstrated the favorable effects of HBOT on nerve recovery both clinically and electrophysiologically following nerve repair. One HBOT session each day for 5 days after surgical treatment can decrease morbidity and facilitate recovery.

Implantation and Control of Wireless, Battery-free Systems for Peripheral Nerve Interfacing.

Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.

SURGICAL TREATMENT OF PERIPHERAL NERVES COMBAT WOUNDS OF THE EXTREMITIES.

OBJECTIVE: The aim: Improving the effectiveness of patients' treatment with combat injuries of the peripheral nervous system, which consists in the application and development of new methods of reconstructive interventions, optimizing a set of therapeutic and diagnostic measures for the most effective management of this category of patients with peripheral nerve injury. PATIENTS AND METHODS: Materials and methods: The research is based on the results of surgical treatment of 138 patients with combat injuries of peripheral nerves for the period from 2014 to 2020. The mean age was 33.5 ± 2.1 years. Patients were treated for 1 to 11 months after injury (median - 8 months). Damage to the sciatic nerve was observed in 26.1%, ulnar - in 20.3%, median - in 18.8%, radial - in 15.9%, tibial - in 10.9%, common peroneal nerve - in 8% of cases. RESULTS: Results: It was shown that in all patients was significantly improved the recovery of all nerves. In the period from 9 to 12 months, the degree of recovery of motor function to M0-M2 was observed in 40.6%, to M3 - in 35.5%, to M4 - in 16.7%, to M5 - in 7,2%. The degree of recovery of sensitivity to S0-S2 was observed in 36.2%, to S3 - in 42.8%, to S4 - in 17.4%, to S5 - in 3.6%. Regression of pain syndrome after surgery was observed in 81.2% of patients. CONCLUSION: Conclusions: The results of surgical treatment of peripheral nerves gunshot injury are generally worse than other types of nerve injuries. The best results of surgical treatment of combat trauma of peripheral nerves are obtained in patients with sciatic nerve damage.

Acute intermittent hypoxia enhances regeneration of surgically repaired peripheral nerves in a manner akin to electrical stimulation.

The intrinsic repair response of injured peripheral neurons is enhanced by brief electrical stimulation (ES) at time of surgical repair, resulting in improved regeneration in rodents and humans. However, ES is invasive. Acute intermittent hypoxia (AIH) - breathing alternate cycles of regular air and air with ~50% normal oxygen levels (11% O2), considered mild hypoxia, is an emerging, promising non-invasive therapy that promotes motor function in spinal cord injured rats and humans. AIH can increase neural activity and under moderately severe hypoxic conditions improves repair of peripherally crushed nerves in mice. Thus, we posited an AIH paradigm similar to that used clinically for spinal cord injury, will improve surgically repaired peripheral nerves akin to ES, including an impact on regeneration-associated gene (RAG) expression-a predictor of growth states. Alterations in early RAG expression were examined in adult male Lewis rats that underwent tibial nerve coaptation repair with either 2 days AIH or normoxia control treatment begun on day 2 post-repair, or 1 h ES treatment (20 Hz) at time of repair. Three days post-repair, AIH or ES treatments effected significant and parallel elevated RAG expression relative to normoxia control at the level of injured sensory and motor neuron cell bodies and proximal axon front. These parallel impacts on RAG expression were coupled with significant improvements in later indices of regeneration, namely enhanced myelination and increased numbers of newly myelinated fibers detected 20 mm distal to the tibial nerve repair site or sensory and motor neurons retrogradely labeled 28 mm distal to the repair site, both at 25 days post nerve repair; and improved return of toe spread function 5-10 weeks post-repair. Collectively, AIH mirrors many beneficial effects of ES on peripheral nerve repair outcomes. This highlights its potential for clinical translation as a non-invasive means to effect improved regeneration of injured peripheral nerves.

Intraoperative Ultrasound for Peripheral Nerve Applications.

Offering real-time, high-resolution images via intraoperative ultrasound is advantageous for a variety of peripheral nerve applications. To highlight the advantages of ultrasound, its extraoperative uses are reviewed. The current intraoperative uses, including nerve localization, real-time evaluation of peripheral nerve tumors, and implantation of leads for peripheral nerve stimulation, are reviewed. Although intraoperative peripheral nerve localization has been performed previously using guide wires and surgical dyes, the authors' approach using ultrasound-guided instrument clamps helps guide surgical dissection to the target nerve, which could lead to more timely operations and shorter incisions.

Regulation of Peripheral Nerve Stimulation Technology.

The number of peripheral nerve stimulation (PNS) indications, targets, and devices is expanding, yet the development of the technology has been slow because many devices used for PNS do not have formal regulatory approval. Manufacturers have not sought Food and Drug Administration (FDA) approval for PNS devices because of a perceived lack of interest amongst practitioners and patients. Without FDA approval, companies cannot invest in marketing to educate the implanters and the patients about the benefits of PNS in the treatment of chronic pain. Violation of this has resulted in governmental investigation and prosecution. Most of the PNS devices currently used to treat chronic pain are FDA approved for epidural spinal cord stimulation. Many of the complications seen in PNS surgery can be attributed to the lack of purpose-built hardware with FDA approval. Despite the lack of regulatory approval, there are insurance companies that approve PNS procedures when deemed medically necessary. As the targets and indications for PNS continue to expand, there will be an even greater need for customized technological solutions. It is up to the medical device industry to invest in the design and marketing of PNS technology and seek out FDA approval. Market forces will continue to push PNS into the mainstream and physicians will increasingly have the choice to implant devices specifically designed and approved to treat chronic peripheral nerve pain.

Peripheral Nerve Stimulation for Back Pain.

Peripheral nerve stimulation (PNS) generally refers to stimulation of a named nerve via direct placement of a lead next to the nerve either via a percutaneous or open approach; in peripheral nerve field stimulation (PNFS), leads are subcutaneously placed to stimulate the region of affected nerves, cutaneous afferents, or the dermatomal distribution of the nerves which converge back to the spinal cord. Recently, there has been a renewed interest in using the PNS approach for many otherwise refractory pain conditions; however, PNFS appears to be more effective for the management of low back pain and therefore more attractive. Here we discuss procedural details of PNFS trial and implant, and provide scientific and clinical rationale for placing PNFS electrodes at a certain depth under the skin. We also summarize results of published studies on use of PNFS in the management of low back pain and list the criteria that are used for proper patient selection. Our experience and the published studies provide evidence that PNFS is a safe and well-tolerated pain control option for intractable pain conditions, including chronic low back pain. Notably, achieving efficacious pain relief relies on correct patient selection and the optimal placement of the leads, ensuring, in particular, a lead depth of 10-12 mm from the surface to maximize the target sensation (mediated by fast-adapting Aß fibers) of PNFS, which is believed to be most effective for the pain relief.

Peripheral Nerve Stimulation for Pain in Extremities: An Update.

Pain in extremities may occur in a variety of central and peripheral neuropathic and nociceptive syndromes, some of which may respond to central neuromodulation procedures. Peripheral neuromodulation techniques, either as a stand-alone therapy or as an adjuvant to spinal cord stimulation, may be particularly effective when the pain is localized to a part of a single extremity or when the source of the pain is related to the malfunction of a known peripheral nerve. Further, peripheral neuromodulation is used to treat disorders in which central simulation fails to provide discrete therapeutic paresthesia. Despite the fact that there are only a few neuromodulatory devices designed specifically for the periphery, clinical experiences are growing, and here we provide a clinical update on use of peripheral nerve stimulation (PNS) in management of chronic pain in extremities. Historical PNS strategies and innovative methods are reviewed and highlighted in this chapter. With the upcoming technological advances and new stimulation paradigms, along with clear updated guidelines statements, the utilization of PNS will likely continue to increase and improve the management of chronic pain syndromes in the extremities. The potential success of the novel devices specifically designed to target the peripheral nervous system is expected to positively impact and promote the use of PNS in treatment of chronic pain.

Peripheral Neuromodulation to Treat Postamputation Pain.

Some of the more common peripherally mediated pain disorders are postamputation stump pain and phantom pain. These disabling conditions have proven difficult to treat. Here we aim to illustrate an option to treat postamputation pain using peripheral neurostimulation techniques. Traditional peripheral neuromodulation techniques use standard stimulation parameters and work by stimulation of nerve tissues which are then felt by the patient as a tingling sensation or paresthesia. Recently introduced high-frequency (10 kHz) electrical nerve block [HFAC (high-frequency alternating current) block] via a surgically implanted peripheral nerve cuff electrode results in true conduction block which actually blocks action potentials emanating from the painful neuroma and thus suppresses pain without tingling or paresthesia felt by the patient. In a recently completed 10-patient pilot study, the average pain level decreased from a score of 5.7 to 1.4 (out of 10) after HFAC block therapy with 85% of all testing sessions yielding a >50% pain reduction; a very significant reduction in the use of opioid and other analgesics was also noted, with all tested patients either stopping or decreasing their analgesic intake significantly. Patients achieved meaningful and significant pain reduction throughout the study, and patients who had phantom pain (in addition to stump pain) that responded to local anesthetic injections also responded favorably with HFAC block, presumably because in these particular patients, the phantom symptoms were peripherally generated. Each of the tested patients reported that HFAC block provided the most significant amount of pain reduction they had ever experienced when compared to other pain modalities tried since their amputations. The high-frequency electric nerve block technique is currently investigational pending FDA clearance. The next step for this modality is a pivotal trial, with the goal of having this therapy available to the mass market upon FDA clearance.

Peripheral Neurostimulation with a Microsize Wireless Stimulator.

Implementation of wireless technology enables tremendous reduction in the size of implantable neurostimulator devices. Without the need for tethering to an implantable pulse generator, a multitude of clinical applications can be envisioned, utilizing safe, rapidly implanted, economical, and culturally sensitive methods. External pulse generators providing power to implanted microsize wireless leads and/or contact pairs can be incorporated into belts, fabric, jewelry, and other suitable and convenient accoutrements. Microsized wireless neurostimulator lead placements can provide neuromodulation therapies without mechanically compromising normal physiological function in numerous anatomical locations not so accessible now. Avoiding implantation of the pulse generator dramatically reduces the expense of these therapies and can potentially lead to wider global access of care for neuromodulation in general.

Electrical stimulation enhances sensory recovery: a randomized controlled trial.

OBJECTIVE: Brief postsurgical electrical stimulation (ES) has been shown to enhance peripheral nerve regeneration in animal models following axotomy and crush injury. However, whether this treatment is beneficial in humans with sensory nerve injury has not been tested. The goal of this study was to test the hypothesis that ES would enhance sensory nerve regeneration following digital nerve transection compared to surgery alone. METHODS: Patients with complete digital nerve transection underwent epineurial nerve repair. After coaptation of the severed nerve ends, fine wire electrodes were implanted before skin closure. Postoperatively, patients were randomized to receiving either 1 hour of 20Hz continuous ES or sham stimulation in a double-blinded manner. Patients were followed monthly for 6 months by a blinded evaluator to monitor physiological recovery of spatial discrimination, pressure threshold, and quantitative small fiber sensory testing. Functional disability was measured using the Disability of Arm, Shoulder, and Hand questionnaire. RESULTS: A total of 36 patients were recruited, with 18 in each group. Those in the ES group showed consistently greater improvements in all sensory modalities by 5 to 6 months postoperatively compared to the controls. Although there was a trend of greater functional improvements in the ES group, it was not statistically significant (p > 0.01). INTERPRETATION: Postsurgical ES enhanced sensory reinnervation in patients who sustained complete digital nerve transection. The conferred benefits apply to a wide range of sensory functions.

Selective peripheral denervation for cervical dystonia: long-term follow-up.

OBJECTIVE: 61 procedures with selective peripheral denervation for cervical dystonia were retrospectively analysed concerning surgical results, pain, quality of life (QoL) and recurrences. METHODS: The patients were assessed with the Tsui torticollis scale, Visual Analogue Scale (VAS) for pain and Fugl-Meyer scale for QoL. Evaluations were performed preoperatively, early postoperatively, at 6 months, then at a mean of 42 (13-165) months. All patients underwent electromyogram at baseline, which was repeated in cases who presented with recurrence of symptoms after surgery. RESULTS: Six months of follow-up was available for 55 (90%) of the procedures and late follow-up for 34 (56%). The mean score of the Tsui scale was 10 preoperatively. It improved to 4.5 (p<0.001) at 6 months, and 5.3 (p<0.001) at late follow-up. VAS for pain improved from 6.5 preoperatively to 4.2 (p<0.001) at 6 months and 4 (p<0.01) at late follow-up. The Fugl-Meyer score for QoL improved from 43.3 to 46.6 (p<0.05) at 6 months, and to 51.1 (p<0.05) at late follow-up. Major reinnervation and/or change in the dystonic pattern occurred following 29% of the procedures, and led in 26% of patients to reoperation with either additional denervation or pallidal stimulation. CONCLUSIONS: Selective peripheral denervation remains a surgical option in the treatment of cervical dystonia when conservative measures fail. Although the majority of patients experience a significant relief of symptoms, there is a substantial risk of reinnervation and/or change in the pattern of the cervical dystonia.

In vivo electrophysiological recording techniques for the study of neuropathic pain in rodent models.

Neuropathic pain develops following nerve injury, and is a chronic pain syndrome that can persist long after repair of a wound or removal of the neurological insult. This condition remains poorly treated, not least because of a lack of mechanism-based therapeutics. Clinically, neuropathic pain is characterized by three major symptoms: thermal or mechanical allodynia (pain sensation in response to previously non-noxious stimuli); hyperalgesia (enhanced pain sensation to noxious stimulation); and spontaneous, ongoing pain. These clinical symptoms can be modeled in rodent neuropathic pain models using behavioral and electrophysiological readouts. This unit describes techniques designed to record pathophysiological electrical activity associated with neuropathic pain at the level of the periphery, in single fibers of primary sensory neurons, and from wide dynamic range (WDR) neurons of the dorsal horn of the spinal cord. These techniques can be employed in both naïve animals and in animal models of neuropathy to investigate fundamental mechanisms contributing to the neuropathic pain state and the site, mode, and mechanism of action of putative analgesics.

A systematic review of peripheral nerve interventional treatments for chronic headaches.

OBJECTIVE: This study aimed to systematically compare the outcomes of different types of interventional procedures offered for the treatment of headaches and targeted toward peripheral nerves based on available published literature. BACKGROUND: Multiple procedural modalities targeted at peripheral nerves are being offered to patients for the treatment of chronic headaches. However, few resources exist to compare the effectiveness of these modalities. The objective of this study was to systematically review the literature to compare the published outcomes and effectiveness of peripheral nerve surgery, radiofrequency (RF) therapy, and peripheral nerve stimulators for chronic headaches, migraines, and occipital neuralgia. METHODS: A broad literature search of the MEDLINE and CENTRAL (Cochrane) databases was undertaken. Relevant studies were selected by 2 independent reviewers and these results were narrowed further by the application of predetermined inclusion and exclusion criteria. Studies were assessed for quality, and data were extracted regarding study characteristics (study type, level of evidence, type of intervention, and number of patients) and objective outcomes (success rate, length of follow-up, and complications). Pooled analysis was performed to compare success rates and complications between modality types. RESULTS: Of an initial 250 search results, 26 studies met the inclusion criteria. Of these, 14 articles studied nerve decompression, 9 studied peripheral nerve stimulation, and 3 studied RF intervention. When study populations and results were pooled, a total of 1253 patients had undergone nerve decompression with an 86% success rate, 184 patients were treated by nerve stimulation with a 68% success rate, and 131 patients were treated by RF with a 55% success rate. When compared to one another, these success rates were all statistically significantly different. Neither nerve decompression nor RF reported complications requiring a return to the operating room, whereas implantable nerve stimulators had a 31.5% rate of such complications. Minor complication rates were similar among all 3 procedures. CONCLUSIONS: Of the 3 most commonly encountered interventional procedures for chronic headaches, peripheral nerve surgery via decompression of involved peripheral nerves has been the best-studied modality in terms of total number of studies, level of evidence of published studies, and length of follow-up. Reported success rates for nerve decompression or excision tend to be higher than those for peripheral nerve stimulation or for RF, although poor study quantity and quality prohibit an accurate comparative analysis. Of the 3 procedures, peripheral nerve stimulator implantation was associated with the greatest number of complications. Although peripheral nerve surgery seems to be the interventional treatment modality that is currently best supported by the literature, better controlled and normalized high-quality studies will help to better define the specific roles for each type of intervention.

Most effective adjuvant treatments after surgery in peripheral nerve laceration: Systematic review of the literature on rodent models.

Surgical repair alone does not lead to satisfactory recovery after nerve laceration injury, yet no adjuvant clinical treatments are available. The goal of this review is to systematically survey all adjuvant treatments after surgery investigated in rat and mouse models. Both PubMed and Embase were explored with a systematic bibliographic search algorithm. Inclusion criteria consisted of treatments applied to rats or mice after complete transection and microsurgical repair of lower-limb motor or mixed nerves. Effect size statistics enabled numerical comparison between outcomes of treated and untreated animals and ranked the best treatments. 1,553 articles were found according to our search strategies, and 22 of them corresponded to our pre-defined inclusion criteria. After data extraction and analysis, the top 3 adjuvant strategies in terms of combined average effect size were citicoline, neurotrophin-4, and nitric oxide synthesis inhibitor, with values of 5.52, 5.14 and 4.08, respectively. Definitive treatment comparison was difficult due to the lack of uniformity in outcome evaluation in the experiments performed. Animal studies, comparing treatments administered within the same experimental protocol, are needed to truly assess efficiency and to provide solid recommendations for future clinical investigation.

New synthetic prosthesis for peripheral nerve injuries: an experimental pilot study.

INTRODUCTION: Even the most modern technology has failed to induce satisfactory functional regeneration of traumatically severed peripheral nerves. Delayed neural regeneration and in consequence, slower neural conduction seriously limit muscle function in the area supplied by the injured nerve. This study aimed to compare a new nerve coaptation system involving an innovative prosthesis with the classical clinical method of sutured nerve coaptation. Besides the time and degree of nerve regeneration, the influence of electrostimulation was also tested. METHODS: The sciatic nerve was severed in 14 female Göttingen minipigs with an average weight of 40.4 kg. The animals were randomized into 2 groups: One group received the new prosthesis and the other underwent microsurgical coaptation. In each group, according to the randomization a part of the animals received postoperative electrostimulation. Postoperative monitoring and the stimulation schedule covered a period of 9 months, during which axonal budding was evaluated monthly. RESULTS: The data from the pilot study indicate that results with the nerve prosthesis were comparable with those of conventional coaptation. CONCLUSION: The results indicate that implantation of the nerve prosthesis allows for good and effective neural regeneration. This new and simple treatment option for peripheral nerve injuries can be performed in any hospital with surgical facilities as it does not involve the demanding microsurgical suture technique that can only be performed in specialized centers.

Otfrid Foerster (1873-1941)--self-taught neurosurgeon and innovator of reconstructive peripheral nerve surgery.

Otfrid Foerster (1873-1941) became a self-taught neurosurgeon during and after WW I, playing a critical role in the development of peripheral nerve reconstruction. Although best known for describing dermatomes, he published over 300 articles on the nervous system. Confronted by thousands of nerve injuries during WW I, as well as poor results and disinterest from his surgical colleagues, Foerster began performing neurolysis and tension-free nerve repairs himself under emergency conditions. He pioneered grafting motor nerve defects by expendable cutaneous nerves (e.g., sural) and performed intraplexal neurotizations and various nerve transfers, such as the pectoral, subscapular, long thoracic, and thoracodorsal nerves in brachial plexus injuries. Foerster championed rehabilitation, recognizing the potential of electrostimulation and physiotherapy to influence cortical reorganization (brain plasticity) and improve recovery after nerve injury. Foerster died from tuberculosis in 1941, leaving a rich reconstructive peripheral nerve legacy; his innovative and visionary spirit serves as a role model.

[Surgical procedures for neuropathic pain].

Different surgical procedures are available for the treatment of many neuropathic pain syndromes. These surgical procedures can be divided into 2 main sections: non-destructive and destructive procedures. In recent years, the non-destructive neurostimulation method has undergone rapid development. Neurostimulation can be applied to a large part of the nervous system including the brain, spinal cord, and peripheral nerves. Spinal cord stimulation has become a dominant pain relief modality because of its minimal invasiveness and the development of a multi-contact stimulating electrode system powered by a multi-programmable and rechargeable stimulator. Currently, destructive surgical procedures have a limited range of indications for pain control. However, the advantages of destructive procedures over non-destructive ones include continuous pain reduction without implantation of a stimulation system. Each of the surgical procedures has great potential for providing patients with significant relief from neuropathic pain.